Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG

Hisataka Kobayashi, Tae M. Yoo, Debra Drumm, Meyoung Kon Kim, Bao Fu Sun, Nhat Le, Keith O. Webber, Ira Pastan, Thomas A. Waldmann, Chang H. Paik, Jorge A. Carrasquillo

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13 Citations (Scopus)

Abstract

Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

Original languageEnglish
Pages (from-to)1955-1961
Number of pages7
JournalCancer Research
Volume57
Issue number10
Publication statusPublished - 1997 May 15
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kobayashi, H., Yoo, T. M., Drumm, D., Kim, M. K., Sun, B. F., Le, N., Webber, K. O., Pastan, I., Waldmann, T. A., Paik, C. H., & Carrasquillo, J. A. (1997). Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG. Cancer Research, 57(10), 1955-1961.